Methods of treating medical conditions by neuromodulation of the sympathetic nervous system

ABSTRACT

The present invention is directed to systems and methods for treating respiratory or pulmonary medical conditions by neuromodulation of a target site of the sympathetic nervous system and preferably a target site in communication with a sympathetic nerve chain. A system for treating a respiratory or pulmonary medical condition incorporating a closed-loop feedback system is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. applicationSer. No. 10/495,766 filed on Oct. 23, 2002, which is acontinuation-in-part of U.S. Ser. No. 10/001,923, filed on Oct. 23,2001, now U.S. Pat. No. 6,885,888, which is a continuation-in-part ofU.S. Ser. No. 09/488,999, now U.S. Pat. No. 6,356,786 filed on Jan. 20,2000; 09/490,617, now U.S. Pat. No. 6,438,423, filed on Jan. 25, 2000;Ser. No. 09/511,839, now U.S. Pat. No. 6,356,787, filed on Feb. 24,2000; and Ser. No. 09/511,841 filed on Feb.24, 2000 (abandoned). Thepresent invention also claims priority to U.S. Provisional ApplicationNos. 60/567,441, filed on May 4, 2004, 60/608,420, filed on Sep. 10,2004, and 60/608,513 filed on Sep. 10, 2004. All of the above-referencedapplications are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to methods of treating medical conditionsby electrical and/or chemical neuromodulation of target sites in thesympathetic nervous system.

BACKGROUND OF THE INVENTION

Neuromodulation involves an array of therapeutic approaches applied tothe brain, cranial nerves, spinal cord and all associated nerves andneural structures in the human body to treat various human disorders.Neuromodulation can involve lesioning, electricalstimulation/modulation, chemical stimulation/modulation including genetherapy and administration of stem cells. Electrical stimulation ofneural tissue is becoming an increasingly preferred form of therapy forcertain neurological conditions and disorders where existing therapiesgenerate intolerable side effects, require repeated administration oftreatment, or are simply ineffective in a subset of patients. Electricalstimulation provides distinct advantages over surgical lesioningtechniques since electrical stimulation is a reversible and adjustableprocedure that provides continuous benefits as the patient's diseaseprogresses and the patient's symptoms evolve.

Currently, electrical stimulation of peripheral nerves and the spinalcord is approved for treatment of neuropathic pain. With respect to deepbrain targets, electrical stimulation of the subthalamic nucleus and theglobus pallidus intema is approved for treatment of Parkinson's diseaseand electrical stimulation of the ventral intermediate nucleus isapproved for treatment of essential tremor.

There remains a need for further forms of neuromodulation to treat theseand other disorders.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a system for treating amedical condition comprising a therapy delivery device for positioningat a target site of the sympathetic nervous system and a controller incommunication with the therapy delivery device for enabling the therapydelivery device to deliver therapy to the target site to treat themedical condition. In a preferred embodiment, the target site is incommunication with the sympathetic nerve chain. The therapy deliverydevice can be a stimulation lead for delivering electricalneuromodulation or a drug port for delivering chemical neuromodulationto the target site.

The present invention also provides a system for treating a medicalcondition comprising a therapy delivery device for applying a therapysignal on a target site in the sympathetic nervous system. The systemalso include a sensor for detecting a bodily activity associated withthe medical condition and generating a sensor signal. The system alsoincludes a controller in communication with the therapy delivery deviceand the sensor for activating the therapy delivery device to initiateapplication of the therapy signal to the target site or to adjustapplication of the therapy signal to the target site in response to thesensor signal. The therapy signal can be an electrical signal inembodiments where the therapy delivery device is a stimulation lead anda chemical signal in embodiments where the therapy delivery device is adrug port.

The present invention also provides a method for treating a medicalcondition comprising placing a therapy delivery device on a target siteof the sympathetic nervous system, preferably a target site incommunication with a sympathetic nerve chain, and activating the therapydelivery device to deliver therapy to the target site to treat themedical condition.

The medical conditions that can be treated by the systems and methods ofthe present invention include skeletal, immunological,vascular/hemotological, muscular/connective, neurological, visual,auditory/vestibular, dermatological, endocrinological, olfactory,cardiovascular, genitourinary, psychological, gastrointestinal,respiratory/pulmonary, inflammatory and neoplastic medical conditions.

The present invention also provide methods of stabilizing and optimizingbodily functions perioperatively and/or post-operatively by stimulatinga target site in communication with a sympathetic nerve chain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a therapy delivery device positioned at a target site of thesympathetic nervous system according to systems and methods of thepresent invention.

FIG. 2 is a schematic illustration of the components which may be usedin a controller of the present invention.

FIG. 3 is a block diagram of an algorithm to determine action which maybe taken by the controller microprocessor in response to sensor input.

FIG. 4 is a schematic illustration of a patient lying in the lateraldecubitus position having one visualization port in the fifthintercostal space at the mid-axillary line and two instrument ports atthe fourth and fifth intercostal space at the anterior and posterioraxillary lines, respectively.

FIG. 5 is an axial cross section view of the upper thoracic regionincluding one visualization port and two instrument ports wherein thetwo instrument ports have disposed therethrough endoscopic instrumentsaccessing the ipsilateral paravertebral region where the sympatheticnerve chain lies.

FIG. 6 is an exposed view of the left hemithorax displaying oneinstrument tenting the parietal pleura while the second endoscopicinstrument is incising the parietal pleura to expose the sympatheticnerve chain.

FIG. 7 is a side view of an exposed superior thoracic ganglia in which atherapy delivery device is disposed adjacent thereto.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides systems and methods for treating medicalconditions by neuromodulation of a target site of a sympathetic nervoussystem and preferably neuromodulation of a target site in communicationwith a sympathetic nerve chain.

The sympathetic nervous system is a division of the autonomic nervoussystem and includes the sympathetic nerve chains and its associateddirect and indirect input and output nerve branches, nerve clusters,nerve aggregates, and nerve plexuses located, for example, in the skull,base of the skull, neck, thoracic, abdominal, and pelvic cavities, andtheir associated arterial and venous structures. The sympathetic nervechain (also known as the sympathetic nerve trunk) is a long ganglionatednerve strand along each side of the vertebral column that extends fromthe base of the skull to the coccyx. Each sympathetic nerve chain isconnected to each spinal nerve by gray rami and receives fibers from thespinal cord through white rami connecting with the thoracic and upperlumbar spinal nerves. A sympathetic nerve chain has paravertebralganglia that are connected by a paravertebral sympathetic chain. Targetsites in communication with the sympathetic nerve chain, according tothe present invention, are target sites in the nervous system havingfibers that project to and/or from the sympathetic nerve chain. Examplesof such target sites include the superior cervical, middle cervical,vertebral, inferior cervical and cervicothoracic ganglia, spinal cordsegments T1 to L3; sympathetic ganglia (including paravertebral gangliaand prevertebral ganglia), paravertebral sympathetic chain, thoracic andlumbar sympathetic ganglia, nerve plexuses in communication withsympathetic ganglia, dorsal roots, ventral roots, dorsal root ganglia,dorsal rami, ventral rami, white rami communicans, gray ramicommunicans, and recurrent meningeal branches, all emerging from spinalcord segments T1 to L3; T1 to L3 spinal nerves; and any combination ofthe above from one or both of the sympathetic nerve chains. Thoracic andlumbar ganglia and prevertebral ganglia and their associated sympatheticstructures include the cardiac, celiac, mesenteric (superior andinferior), renal, hypogastric, and intermesenteric (abdominal aortic)ganglia as well as ganglia associated with glands such as hepatic oradrenal glands. Nerve plexuses include prevertebral plexuses such as thesuperior and inferior hypogastric (pelvic) plexus. Target sites alsoinclude the thoracic, lumbar, and sacral splanchnic nerves. The systemsand methods of the present invention for treating medical conditionsencompass neuromodulation of any combination of one or more target sitesof the sympathetic nervous system, including any combination of one ormore target sites in communication with the sympathetic nerve chain. Thesystems and methods of the present invention also encompass ipsilateral,contralateral, and bilateral neuromodulation.

As used herein, the term “treating” a medical condition encompassestherapeutically regulating, preventing, improving, alleviating thesymptoms of, reducing the effects of and/or diagnosing the medicalcondition. As used herein, the term “medical condition” encompasses anycondition, disease, disorder, function, abnormality, or deficitinfluenced by the autonomic nervous system. Further, the systems andmethods of the present invention can be used to treat more than onemedical condition concurrently. Non-limiting examples of medicalconditions that can be treated according to the present inventioninclude genetic, skeletal, immunological, vascular or hematological,muscular or connective tissue, neurological, ocular, auditory orvestibular, dermatological, endocrinological, olfactory, cardiovascular,genitourinary, psychological, gastrointestinal, respiratory/pulmonary,neoplastic, or inflammatory medical conditions. Further, the medicalcondition can be the result of any etiology including vascular,ischemic, thrombotic, embolic, infectious (including bacterial, viral,parasitic, fungal, abscessal), neoplastic, drug-induced, metabolic,immunological, collagenic, traumatic, surgical, idiopathic,endocrinological, allergic, degenerative, congenital, or abnormalmalformational causes.

The present invention also encompasses enhancing the therapeutic effectsof other therapies, such as methods and systems working in conjunctionwith a pharmaceutical agent or other therapies to augment, enhance,improve, or facilitate other therapies (adjunctive therapies) as well asreducing/minimize and counteracting side effects, complications andadverse reactions for any therapies involved in treating theabove-mentioned medical conditions. For example, the methods and systemsof the present invention may be used for a cancer patient undergoingchemotherapy utilizing stimulation to minimize the adverse effects ofchemotherapy. In contrast, the methods and systems can be used toenhance chemotherapy.

With respect to treating genetic medical conditions, such medicalconditions can affect single organs, organ systems, or multiple organsin multiple organ systems.

With respect to treating skeletal medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the skeletal system such as, for example, bones, joints, or thesynovium. Non-limiting examples of such skeletal medical conditionsinclude fractures, osteoporosis, osteomalacia, osteopenia, arthritis,and bursitis.

With respect to treating immunological, inflammatory, and allergicmedical conditions, such medical conditions can involve any medicalconditions related to the components of the immune system such as, forexample, the spleen or thymus. Non-limiting examples of immunologicalmedical conditions include immuno-suppressed states, immuno-compromisedstates, auto-immune disorders, drug-related allergy, an environmentalallergy, or hypogamaglobunimia.

With respect to treating vascular or hematological medical conditions,such medical conditions can involve any medical conditions related tothe components of the vascular system such as, for example, thearteries; arterioles; veins; venules; capillaries; lymph nodes; bloodincluding plasma, white blood cells, red blood cells, and platelets.Non-limiting examples of vascular/hematological medical conditionsinclude anemia, thrombocytosis, thrombocytopenia, neutropenia,hemophilia, lymphedema, thrombosis, vasculitis, venous insufficiency,arterial dissection, peripheral edema, blood loss, vascularinsufficiency, hypercoagulable states, stroke, vasospasms, and disordersof vascular tone effecting perfusion. The vasculitis may be multifocal,systemic, or limited to the central nervous system. The hypercoagulablestate may be factor V deficiency or anti-thrombin deficiency, amongothers. The stroke may result from cerebrovascular disease and/orischemia from decreased blood flow/oxygenation second to occlusive orthromboembolic disease. The vasospasms may be secondary to aneurismalsubarachnoid hemorrhage or vasospasm secondary to other etiologies.

With respect to treating muscular/connective tissue medical conditions,such medical conditions can involve any medical conditions related tothe components of the muscular/connective tissue system such as, forexample, smooth or striated muscles, tendons, ligaments, cartilage,fascia, and fibrous tissue. Non-limiting examples of muscular medicalconditions include myopathy, muscular dystrophy, weakness, and muscleatrophy. The muscle atrophy may be caused by degenerative muscledisease, nerve injury, disuse atrophy or stroke. Non-limiting examplesof connective tissue medical conditions include scleroderma, rheumatoidarthritis, lupus, Sjogren's syndrome, fibromyalgia, myositis, myofascialpain syndrome, and collagen vascular disease. The collagen vasculardisease may be lupus or rheumatoid arthritis.

With respect to treating neurological medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the nervous system such as, for example, the brain including thecerebellum, brain stem, pons, midbrain, medulla; the spinal cord;peripheral nerves; peripheral ganglia; and nerve plexuses. Non-limitingexamples of neurological conditions include Alzheimer's disease,epilepsy, multiple sclerosis, ALS, Guillan Barre, stroke, cerebralpalsy, intracerebral hemorrhage, dementia, vertigo, tinnitus, diplopia,cerebral vasospasm, aneurysm, atriovenous malformation, brainmalformations, Parkinson's disorder, multi-system atrophy,olivopontocerebellar degeneration, familial tremor dystonia includingcervical dystonia, torticollis, facial dystonia, blepharospasms,spasmodic dysphonia, radiculopathy, neuropathy, sleep disorders,disorders of temperature regulation in the body and extremities,postherpetic neuralgia involving the face, head, body or extremities.The neuropathy may be caused by fracture, crush injury, compressiveinjury, repetitive movement injury, diabetes, trauma, alcohol,infection, or hereditary. The sleep disorder may be sleep apnea,restless leg syndrome, narcolepsy, snoring, insomnia, and drowsiness.

With respect to treating ocular medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the visual system such as, for example, the eye including the lens,iris, conjunctiva, lids, cornea, retina including macula, the vitreouschambers, and the aqueous chambers. Non-limiting examples of ocularmedical conditions include myopia, hyperopia, exopthalmous, astigmatism,corneal ulcer, strabismus, retinitis pigmentosa, retinal tears, maculardegeneration, cataracts, xerophthamia, amblyopia, and astigmatism,glaucoma, blindness, and diplopia.

With respect to treating auditory and vestibular medical conditions,such medical conditions can involve any medical conditions related tothe components of the auditory and vestibular system such as, forexample, the ear including the external ear, the middle ear, the innerear, cochlea, ossicles, tympanic membrane, and semicircular canals.Non-limiting examples of auditory and vestibular medical conditionsinclude otitis, vertigo, hearing loss, dizziness, and tinnitus.

With respect to treating dermatological medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the skin and integumentary system such as, for example, the hair,skin, nails, and sweat glands. Non-limiting examples of dermatologicalmedical conditions include rosacea, eczema, psoriasis, acne, hair loss,hypertrichosis, seborrheic dermatitis, xerotic skin, oily skin,atrophy/dystrophy of the skin, wrinkles, radiation induced damage,vitiligo, and cellulite.

With respect to treating endocrinological medical conditions, suchmedical conditions can involve any medical conditions related to thecomponents of the endocrine system such as, for example, the pancreas,thyroid, adrenal glands, liver, pituitary, and hypothalamus.Non-limiting examples of endocrinological conditions includehypoglycemia, diabetes type I and II, obesity, hyperthyroidism,hypothyroidism, amenorrhea, dysmenorrhea, infertility, impotence,anorgasmia, delayed orgasm, perimenstrual syndrome,hypercholesterolemia, hypertriglycridinemia, Cushing's disease,Addison's disease, malabsorption syndrome, dysautonomia, chronic fatiguesyndrome, fatigue, heat exhaustion, cold extremities, hot flashes,vasomotor instability, Raynaud's syndrome, hormonal disorders, metabolicdisorders such as gout, disorders of metabolism and metabolic storagediseases where there is an accumulation of abnormal amounts of varioussubstances such as glycogen in glycogen storage diseases, iron inhemochromatosis or copper in Wilson's disease.

With respect to treating olfactory medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the olfactory system such as, for example, the nose, sensory nervesfor smell, and sinuses. Non-limiting examples of olfactory conditionsinclude loss of sense of smell, rhinorrhea, rhinitis, acute sinusitis,chronic sinusitis, or nasal congestion.

With respect to treating cardiovascular medical conditions, such medicalconditions can involve any medical conditions related to the componentsof the cardiovascular system such as, for example, the heart and aorta.Non-limiting examples of cardiovascular conditions includepost-infarction rehabilitation, valvular disease, myocardial infarction,arrhythmia, heart failure, angina, microvascular ischemia, myocardialcontractility disorder, cardiomyopathy, hypertension, orthostatichypotension, dysautonomia, syncope, vasovagal reflex, carotid sinushypersensitivity, and cardiac structural abnormalities such as septaldefects and wall aneurysms. The cardiomyopathy may be caused byhypertension, alcohol, or by a congenital cause. The hypertension may beessential, primary, secondary, or renal.

With respect to treating genitourinary medical conditions, such medicalconditions may involve any medical conditions related to the componentsof the genitourinary system such as, for example, the ovary, fallopiantube, uterus, vagina, penis, testicles, kidney, bladder, ureter, andurethra. Non-limiting examples of genitourinary medical conditionsinclude impotence, dysmenorrhea, amenorrhea, anorgasmia, delayed orgasm,endometriosis, infertility, uterine fibroids, ovarian cysts, spasticbladder, flaccid bladder, interstitial cystitis, polycystic kidneydisease, nephrotic syndrome, uremia, glumerolonephritis, renal failure,urinary incontinence or hesitancy, uremia, nephrolithiasis, and benignprosthetic hyperplasia.

With respect to treating psychological medical conditions, non-limitingexamples of such medical conditions include Tourette's syndrome, autism,mental retardation, stress, anxiety, depression, bipolar disorder,mania, schizophrenia, a personality disorder, a phobia, hallucinations,delusions, psychosis, addictions, and other affective disorders. Theaddiction may be to substances or behavior. The substance may bealcohol, cigarettes, or drugs.

With respect to treating gastrointestinal medical conditions, suchmedical conditions can involve any medical conditions related to thecomponents of the gastrointestinal system such as, for example, themouth, esophagus, stomach, small intestine, large intestine, rectum,liver, gall bladder, bile ducts, and pancreas. Non-limiting examples ofgastrointestinal medical conditions include hepatic failure, hepatitis,cirrhosis, dumping syndrome, cirrhosis, gastric or duodenal ulcer,irritable bowel syndrome, colitis, diverticulosis, diverticulitis,emesis, hyper emesis gravidum, bowel incontinence, constipation,diarrhea, abdominal cramps, gastro esophageal reflux, esophagealdysmotility, gastric dysmotility, cholecystitis, gall stones, pancreaticinsufficiency, gas, bloating, and gastritis.

With respect to treating respiratory/pulmonary medical conditions, suchmedical conditions can involve any medical conditions related to thecomponents of the respiratory system such as, for example, the trachea,bronchus, bronchioles, alveoli, lungs, and capillaries. Non-limitingexamples of respiratory medical conditions include reactive airwaydisease, asthma, emphysema, COPD, and silicosis.

With respect to treating neoplastic processes such processes can beprimary and/or metastatic and can involve the thryoid including themedullary, the liver, the pancreas (including vipoma and insulinoma),leukemia, lymphoma and other non-solid tumors, neoplastic processes ofthe brain, stomach, lung, colon, esophagus, bone, skin including basalcells, squamous cells, and melanoma, the bladder, kidney, prostate,breast, ovaries, uterus, nasopharynx, and sarcoma.

With respect to treating inflammatory disorders, such inflammatorydisorders include, for example, inflammatory bowel disorders such asirritable bowel syndrome and Crohn's disease; and auto-immune disorders,immune disorders and rheumatological disorders.

The present invention also provides methods of treating pain syndromes.Such pain may result from one or more medical conditions comprising:migraine headaches, including migraine headaches with aura, migraineheadaches without aura, menstrual migraines, migraine variants, atypicalmigraines, complicated migraines, hemiplegic migraines, transformedmigraines, and chronic daily migraines; episodic tension headaches;chronic tension headaches; analgesic rebound headaches; episodic clusterheadaches; chronic cluster headaches; cluster variants; chronicparoxysmal hemicrania; hemicrania continua; post-traumatic headache;post-traumatic neck pain; post-herpetic neuralgia involving the head orface; pain from spine fracture secondary to osteoporosis; arthritis painin the spine, headache related to cerebrovascular disease and stroke;headache due to vascular disorder; reflex sympathetic dystrophy,cervicalgia; glossodynia, carotidynia; cricoidynia; otalgia due tomiddle ear lesion; gastric pain; sciatica; maxillary neuralgia;laryngeal pain, myalgia of neck muscles; trigeminal neuralgia;post-lumbar puncture headache; low cerebro-spinal fluid pressureheadache; temporomandibular joint disorder; atypical facial pain;ciliary neuralgia; paratrigeminal neuralgia; petrosal neuralgia; Eagle'ssyndrome; idiopathic intracranial hypertension; orofacial pain;myofascial pain syndrome involving the head, neck, and shoulder; chronicmigraneous neuralgia, cervical headache; paratrigeminal paralysis;sphenopalatine ganglion neuralgia; carotidynia; Vidian neuralgia; andcausalgia. To neuromodulate such pain syndromes, preferably the cervicaland thoracic ganglia are stimulated.

The present invention also provides methods of treating the effects ofaging, burns, trauma, transplantation, radiation damage, bioterrorism,back pain, and body pain.

FIG. 1 provides an illustration of a therapy delivery device 10,according to an embodiment of the present invention positioned at atarget site in the sympathetic nervous system (which in this exemplaryillustration is a ganglia of the sympathetic nerve chain). Therapydelivery device is connected via a stimulation lead/catheter 20 (inembodiments where therapy delivery device is a stimulation lead and drugport respectively) for connection to a controller (not shown). Thetherapy delivery device has a configuration that allows the therapydeliver device to maximize contact with and optimally deliver therapy tothe target site. In embodiments where the therapy delivery device is asympathetic ganglion, preferably the therapy delivery device has aconfiguration as described is PCT Application No. PCT/US03/03003entitled “Delivery Device for Stimulating the Sympathetic Nerve Chain,”which is incorporated by reference herein.

In embodiments where the therapy delivery device is a stimulation leadhaving a lead proximal end, a lead body, and a lead distal end, the leaddistal end comprises at least one electrode. The at least one electrodecan be a plurality of electrodes. The electrodes at the lead distal endcan be either monopolar, bipolar, or multipolar, and can operate as acathode or an anode. The electrode can be composed of but not limited toactivated iridium, rhodium, titanium, or platinum and combinations ofsaid materials. The electrode may be coated with a thin surface layer ofiridium oxide, titanium nitride or other surface modifications toenhance electrical sensitivity. The stimulation lead can also comprisecarbon, doped silicon, or silicon nitride. Each lead distal end can beprovided with a biocompatible fabric “collar” or band about theelectrode periphery to allow it to be more readily sutured or glued intoplace (for electrodes to be secured in this manner). The stimulationlead may be placed permanently or temporarily in the target site toprovide chronic or acute neuromodulation of the target site.

The controller is used to operate and supply power to the therapeuticdelivery device and enable the therapy delivery device to delivery atherapy signal (such as an electrical signal or a chemical signal) tothe target site. The controller may be powered by a battery (which canbe rechargable), an external power supply, a fuel cell, or a batterypack for external use. The controller may also be integral with thetherapeutic delivery device (such as a single stimulation lead/powergenerator). When the therapeutic delivery device is a stimulation lead,the controller may change the output to the electrode by way ofpolarity, pulse width, amplitude, frequency, voltage, current,intensity, duration, wavelength, and/or waveform. When the therapeuticdelivery device is a drug port, the controller may change its outputsuch that a pump, pressure source, or proportionally controlled orificeincreases or decreases the rate at which the pharmaceutical is deliveredto the target site. The controller may operate any number or combinationof electrodes, and pharmaceutical delivery devices, for example thecontroller may be connected to stimulation leads and a peristaltic pumpfor delivering a pharmaceutical to the target site near the stimulationleads. The controller may be implanted within the patient or it may bepositioned by leads outside of the patient. A portion of the controlsystem may be external to the patient's body for use by the attendingphysician to program the implanted controller and to monitor itsperformance. This external portion may include a programming wand whichcommunicates with the implanted controller by means of telemetry via aninternal antenna to transmit parameter values (as may be selectivelychanged from time to time by subsequent programming) selected at theprogrammer unit, such as a computer. The programming wand also acceptstelemetry data from the controller to monitor the performance of thetherapy delivery device.

In embodiments where the controller enables a stimulation lead todeliver an electrical signal to the target site, the electrical signalmay be episodic, continuous, phasic, in clusters, intermittent, upondemand by the patient or medical personnel, or preprogrammed to respondto a sensor. Preferably, the oscillating electrical signal is operatedat a voltage between about 0.1 microvolts to about 20 V. Morepreferably, the oscillating electrical signal is operated at a voltagebetween about 1 V to about 15 V. For microstimulation, it is preferableto stimulate within the range of 0.1 microvolts to about 1 V.Preferably, the electric signal source is operated at a frequency rangebetween about 2 Hz to about 2500 Hz. More preferably, the electricsignal source is operated at a frequency range between about 2 Hz toabout 200 Hz. Preferably, the pulse width of the oscillating electricalsignal is between about 10 microseconds to about 1,000 microseconds.More preferably, the pulse width of the oscillating electrical signal isbetween about 50 microseconds to about 500 microseconds. Preferably, theapplication of the oscillating electrical signal is: monopolar when thestimulation lead is monopolar; bipolar when the stimulation lead isbipolar; and multipolar when the stimulation lead is multipolar. Thewaveform may be, for example, biphasic, square wave, sine wave, or otherelectrically safe and feasible combinations. The electrical signal maybe applied to multiple target sites simultaneously or sequentially.

In embodiments where the controller enables a drug port to deliver achemical signal to the target site, a chemical agent may be delivered tothe target site prior to, concurrent with, subsequent to or instead ofelectrical neuromodulation. The chemical agent may be a neurotransmittermimick; neuropeptide; hormone; pro-hormone; antagonist, agonist,reuptake inhibitor, or degrading enzyme thereof; peptide; protein;therapeutic agent; amino acid; nucleic acid; stem cell or anycombination thereof and may be delivered by a slow release matrix ordrug pump. The delivery of the chemical agent may be continuous,intermittent, chronic, phasic, or episodic. Different chemical agentsmay be utilized to affect different parts of the sympathetic nervoussystem. The chemical agents preferably work on one or more of thereceptor sites of the autonomic nervous system such as the adrenergicreceptors, cholinergic receptors (nicotinic and muscarinic), purinergic,and nitric oxide receptors. Non-limiting examples of chemical agentsinclude, prazosin, yohimbine, atelenol, sulbutamol, and atropine.

The present invention also provides systems for treating medicalconditions incorporating a closed-loop feedback mechanism. Specifically,in such embodiments, the system comprises a therapy delivery device forapplying a therapy signal (which can be an electrical signal or achemical signal) on a target site of the sympathetic nervous system, andpreferably a target site in communication with a sympathetic nervechain. The system further comprises a sensor for detecting a bodilyactivity associated with the medical condition and for generating asensor signal. The system also includes a controller in communicationwith the therapy delivery device for activating the therapy deliverydevice to initiate application of the therapy signal to the target siteor to adjust application of the therapy signal to the target site inresponse to the sensor signal. The bodily activity to be detected by thesensor is any characteristic or function of the body, such as electricalor chemical activity and includes, for example, temperature, respiratoryfunction, heart rate, capillary pressure, venous pressure, perfusion,oxygenation including blood oxygenation levels, oxygen saturationlevels, oxygen consumption, oxygen pressure, water pressure, nitrogenpressure, carbon dioxide pressure in the tissue, circulation (includingblood and lymphatic), electrolyte levels in the circulation/tissue,diffusion or metabolism of various agents and molecules (such asglucose), neurotransmitter levels, body temperature regulation, bloodpressure, blood viscosity, metabolic activity, cerebral blood flow, pHlevels, vital signs, galvanic skin responses, perspiration,electrocardiogram, electroencephalogram, action potential conduction,chemical production, body movement, response to external stimulation,cognitive activity, dizziness, pain, flushing, motor activity includingmuscle tone, visual activity, speech, balance, diaphragmatic movement,chest wall expansion, concentration of certain biologicalmolecules/substances in the body such as, for example, glucose, liverenzymes, electrolytes, hormones, creatinine, medications, concentrationof various cells, platelets, or bacteria. These bodily activities can bemeasured utilizing a variety of methods including but not limited tochemical analysis, mechanical measurements, laser, and fiber-opticanalysis. Non-limiting examples of further tests and bodily activitiesthat can be sensed for categories of medical conditions and specificmedical conditions are provided in TABLE I. Table I is only exemplaryand non-exhaustive and other bodily activities can be sensed, as well asvarious combinations of the sensed activities listed in Table I.

In specific embodiments, the sensors are located on or within the bodyand detect electrical and/or chemical activity. Such activity may bedetected by sensors located within or proximal to the target site,distal to the target site but within the nervous system, or by sensorslocated distal to the target site outside the nervous system. Examplesof electrical activity detected by sensors located within or proximal tothe target site include sensors that measure neuronal electricalactivity, such as the electrical activity characteristic of thesignaling stages of neurons (i.e. synaptic potentials, trigger actions,action potentials, and neurotransmitter release) at the target site andby afferent and efferent pathways and sources that project to and fromor communicate with the target site. For example, the sensors canmeasure, at any signaling stage, neuronal activity of any of theextensive connections of the target site. In particular, the sensors maydetect the rate and pattern of the neuronal electrical activity todetermine the electrical signal to be provided to the lead.

Examples of chemical activity detected by sensors located within orproximal to the target site include sensors that measure neuronalactivity, such as the modulation of neurotransmitters, hormones,pro-hormones, neuropeptides, peptides, proteins, electrolytes, or smallmolecules by the target site and modulation of these substances byafferent and efferent pathways and sources that project to and from thetarget sites or communicate with the target sites.

With respect to detecting electrical or chemical activity of the body bysensors located distal to the target site but still within the nervoussystem, such sensors could be placed in the brain, the spinal cord,cranial nerves, and/or spinal nerves. Sensors placed in the brain arepreferably placed in a layer-wise manner. For example, a sensor could beplaced on the scalp (i.e. electroencephalogram), in the subgaleal layer,on the skull, in the dura mater, in the sub dural layer and in theparenchyma (i.e. in the frontal lobe, occipital lobe, parietal lobe,temporal lobe) to achieve increasing specificity of electrical andchemical activity detection. The sensors could measure the same types ofchemical and electrical activity as the sensors placed within orproximal to the target site as described above.

With respect to detecting electrical or chemical activity by sensorslocated distal to the target site outside the nervous system, suchsensors may be placed in venous structures and various organs or tissuesof other body systems, such as the endocrine system, muscular system,respiratory system, circulatory system, urinary system, integumentarysystem, and digestive system or such sensors may detect signals fromthese various body systems. For example, the sensor may be an externalsensor such as a pulse oximeter, or an external blood pressure, heart,and respiratory rate detector. All the above-mentioned sensing systemsmay be employed together or any combination of less than all sensors maybe employed together.

After the sensor(s) detect the relevant bodily activity associated withthe medical condition, according to the systems of the presentinvention, the sensors generate a sensor signal. The sensor signal isprocessed by a sensor signal processor, which in this embodiment is partof the controller. The controller generates a response to the sensorsignal by activating the therapy delivery device to initiate applicationof the therapy signal or to adjust application of the therapy signal tothe target site. The therapy deliver device then applies the therapysignal to the target site. In embodiments where the therapy deliverydevice is a stimulation lead and the therapy signal is an electricalsignal, activating the stimulation lead to adjust application of theelectrical signal includes terminating, increasing, decreasing orchanging the rate or pattern of a pulsing parameter of the electricalstimulation and the electrical signal can be the respective termination,increase, decrease or change in rate or pattern of the respectivepulsing parameter. In embodiments where the therapy delivery device is adrug port and the therapy signal is a chemical signal, activating thedrug port to adjust application of the chemical signal can be anindication to terminate, increase, decrease or change the rate orpattern of the amount or type of chemical agent administered, and thechemical signal can be the respective initiation, termination, increase,decrease or change in the rate or pattern of the amount or type ofchemical agent administered. The processing of closed-loop feedbacksystems for electrical and chemical stimulation are described in moredetail in respective U.S. Pat. Nos. 6,058,331 and 5,711,316, both ofwhich are incorporated by reference herein.

Closed-loop electrical stimulation, according to the present inventioncan be achieved by a modified form of an implantable SOLETRA, KINETRA,RESTORE, or SYNERGY signal generator available from Medtronic,Minneapolis, Minn. as disclosed in U.S. Pat. No. 6,353,762, the teachingof which is incorporated herein in its entirety, a controller asdescribed in FIG. 2, or utilization of CIO DAS 08 and CIO-DAC 16 Iprocessing boards and an IBM compatible computer available fromMeasurement Computing, Middleboro, Mass. with Visual Basic software forprogramming of alogorithms. With reference to FIG. 2 an illustration ofa non-limiting example of a controller comprising a microprocessor 76such as an MSP430 microprocessor from Texas Instruments Technology,analog to digital converter 82 such as AD7714 from Analog Devices Corp.,pulse generator 84 such as CD1877 from Harris Corporation, pulse widthcontrol 86, lead driver 90, digital to analog converter 88 such asMAX538 from Maxim Corporation, power supply 72, memory 74, andcommunications port or telemetry chip 70 are shown. Optionally, adigital signal processor 92 is used for signal conditioning andfiltering. Input leads 78 and 80 and output lead to lead (therapeuticdelivery device) 91 and drug delivery device (therapeutic deliverdevice) 93 are also illustrated. Additional stimulation leads, sensors,and therapeutic delivery devices may be added to the controller asrequired. As a non-limiting example, inputs from sensors, such as heartrate and blood pressure sensors, are input to analog to digitalconverter 82. Microprocessor 76 receiving the sensor inputs usesalgorithms to analyze the biological activity of the patient and usingHD, Fuzzy logic, or other algorithms, computes an output to pulsegenerator and/or drug delivery device drivers 90 and 94, respectively,to neuromodulate the target site where the therapeutic delivery devicesare placed. The output of analog to digital converter 82 is connected tomicroprocessor 76 through a peripheral bus including address, data andcontrol lines. Microprocessor 76 processes the sensor data in differentways depending on the type of transducer in use. When the signal on thesensor indicates biological activity outside of threshold values, forexample elevated blood pressure or heart rate, programmed by theclinician and stored in a memory, the electrical signal applied throughoutput drivers 90 and 94 of the controller will be adjusted. The outputvoltage or current from the controller are then generated in anappropriately configured form (voltage, current, frequency), and appliedto the one or more therapeutic delivery devices placed at the targetsite for a prescribed time period to reduce elevated blood pressure orheart rate. If the patient's blood pressure or heart rate as monitoredby the system is not outside of the normal threshold limits (hypotensiveor hypertensive, bradycardic or tachycardic), or if the controlleroutput (after it has timed out) has resulted in a correction of theblood pressure or heart rate to within a predetermined threshold range,no further electrical signal is applied to the target site and thecontroller continues to monitor the patient via the sensors. A blockdiagram of an algorithm which may be used in the present invention isshown in FIG. 3.

Referring to FIG. 3, suitably conditioned and converted sensor data 98is input to the algorithm in block 100. The program computes at leastone value of at least one biological activity related to a particularmedical condition such as, for example, blood pressure, heart rate, orcardiac output, and compares the measured value of the biologicalactivity to a pre-determined range of values, which is determined inadvance to be the desired therapeutic range of values. This range isprogrammed into the microprocessor via the telemetry or communicationsport of the controller. The algorithm compares, 110, and then determineswhether or not the measured value lies outside the pre-determined rangeof values, 120. If the measured biological activity value is not outsidethe pre-determined range of values, the program continues to monitor thesensors and reiterates the comparison part of the algorithm. If themeasured biological value is outside of the pre-determined range ofvalues, a determination or comparison is made, 130, as to whether thevalue is too high or too low compared with the pre-determined range. Ifthe biological activity value is too high, an adjustment to thetherapeutic delivery device is made, 150, to lower the biologicalactivity value of the patient by calculating an output signal for pulsegenerator or drug delivery device to deliver a sufficient amount of thepharmaceutical or electrical stimulation to lower the biologicalactivity of the patient. The algorithm continues to monitor thebiological activity following the adjustment. If the biological activityvalue is too low then an adjustment to the therapeutic delivery deviceis made, 140, to raise the biological activity value by calculating anoutput signal for the pulse generator or drug delivery device to delivera sufficient amount of a pharmaceutical or electrical stimulation toraise the biological activity value of the patient. The algorithmcontinues to monitor the biological activity of the patient, 100,following the adjustment. The amount of adjustment made may bedetermined by proportional integral derivative algorithms of byimplementation of Fuzzy logic rules.

With respect to the control of specific electrical parameters, thestimulus pulse frequency may be controlled by programming a value to aprogrammable frequency generator using the bus of the controller. Theprogrammable frequency generator provides an interrupt signal to themicroprocessor through an interrupt line when each stimulus pulse is tobe generated. The frequency generator may be implemented by modelCDP1878 sold by Harris Corporation. The amplitude for each stimuluspulse may be programmed to a digital to analog converter using thecontroller's bus. The analog output is conveyed through a conductor toan output driver circuit to control stimulus amplitude. Themicroprocessor of the controller may also program a pulse width controlmodule using the bus. The pulse width control provides an enabling pulseof duration equal to the pulse width via a conductor. Pulses with theselected characteristics are then delivered from signal generatorthrough a cable and lead to the target site or to a device such as aproportional valve or pump. For some types of sensors, a microprocessorand analog to digital converter will not be necessary. The output fromsensor can be filtered by an appropriate electronic filter in order toprovide a control signal for signal generator. An example of such afilter is found in U.S. Pat. No. 5,259,387 Muscle Artifact Filter,Issued to Victor de Pinto on Nov. 9, 1993, incorporated herein byreference in its entirety.

At the time the therapy delivery device is implanted, the clinicianprograms certain key parameters into the memory of the implanted devicevia telemetry. These parameters may be updated subsequently as needed.The clinician may also program the the range of values for pulse width,amplitude and frequency which the therapy delivery device may use tooptimize the therapy. The clinician may also choose the order in whichthe parameter changes are made. Alternatively, the clinician may electto use default values or the microprocessor may be programmed to usefuzzy logic rules and algorithms to determine output from thetherapeutic delivery device to the patient based on sensor data andthreshold values for the biological activity.

Although the application of sensors to detect bodily activity are partof embodiments of systems of the present invention, the presentinvention also contemplates the relevant bodily activity to be detectedwithout sensors. In such case, the neuromodulation parameters areadjusted manually in response to the clinical course of the disease orreporting by the patient.

In another embodiment, the present invention provides a method ofstabilizing and/or optimizing bodily functions, augmenting function andtreating the various diseases/ disorders listed in Table I by placing atherapy delivery device on a target site of the sympathetic nervoussystem, and preferably a target site in communication with a sympatheticnerve chain, and activating the therapy delivery device to apply atherapy signal (electrical and/or chemical signal) to the target site tostabilize and/or optimize the bodily function as well as to enhance,augment, normalize, regulate, control and/or improve the normal andabnormal functioning of the various body organs/structures/systems (forexample heart, lung, gastrointestinal, genitourinary, vascular, andother systems) that are innervated by the sympathetic nervous system.This method can be performed in the operating room, procedure room orimaging (MRI, CT, X-ray, fluoroscopy or optical imaged guided) suite.The procedures can be carried out peri-operative or post-operative to asurgical operation as well as in an intensive care unit and any othercommonly utilized in-patient and out-patient capacities. Preferably, thesurgical operation includes procedures that may require heart bypassequipment, procedures that may require a respiratory ventilator, orsurgeries where intravenous medications are used during and aftersurgery to influence cardiac and/or pulmonary function. In analternative embodiment, this method is performed in a non-surgicalsetting where intravenous medications are used for sedation, analgesiaand to stabilize cardiac function, such as in the setting of myocardialinfarction.

The present invention also provides a method for minimizing or resolvingside effects and morbidity associated with other therapies used forvarious disorders including medications, surgery, chemotherapy, andradiation.

Neuromodulation of the target sites of the present invention can betemporary or short term, such as less than 10 days, intermediate (10-30days) or chronic (greater than 30 days). Further, the target sites canbe accessed using any of the current approaches used by neurosurgeons,spinal surgeons, cardio-thoracic surgeons, vascular surgeons, abdominalsurgeons, GU surgeons, ENT surgeons, plastic surgeons as well asinterventional radiologists, neurologists, pain management specialists,rehabilitation and physical therapy specialists and anesthesiologists.The procedures involves direct and in-direct placement of the therapydelivery device. This can be achieved using percutaneous, endoscopic,intravascular, or open surgical approach. Furthermore all theseapproaches can be guided by imaging means ofMRI/CT/X-ray/fluoroscopy/optical imaging. A variety of approaches areavailable and practiced routinely by the group of specialists listedabove. Non-limiting and commonly employed procedures are posteriorparavertebral thoracic sympathectomy, thoracoscopic sympathectomy, andretroperitoneal lumbar sympathectomy. Reference is made to “SurgicalManagement of Pain”, Thieme Medical Publishers, Inc. RD 595.5.587 (2001)incorporated in its entirety herein by reference thereto for furtherdetails. For open surgery, anterior supraclavicular, transaxillary, andposterior paravertebral approaches can be used.

A non-limiting example of a method of placing a therapy delivery deviceon a target site of the sympathetic nervous system will now bedescribed. Referring to FIG. 4, a patient 200 is illustrated in thedecubitus position where the hips of the patient 200 are preferablybelow the flexion joint of the operating room table. Subsequent flexionof the table allows some separation of the ribs by dropping thepatient's hips and therefore increasing the intercostal space to workthrough. The ipsilateral arm is abducted on an arm holder. Rotating thetable somewhat anteriorly and using reverse Trendelenburg positioningfurther maximizes the exposure to the superior paravertebral area byallowing the soon to be deflated lung (see FIGS. 5 and 6) to fall awayfrom the apical posterior chest wall. This is the preferred position ofthe patient 200 prior to performing the procedure as this positionexposes the vertebral bodies where the sympathetic nerve chain liesextrapleurally.

The procedure begins with placing the patient 200 under generalanesthesia and intubated via a double lumen endotracheal tube. Thedouble lumen endotracheal tube permits ventilation of one lung andcollapse of the other lung that is to be operated upon without usingcarbon dioxide insufflation. One incision is made in the midaxillaryline in the fifth intercostal space that is identified as port 204. Port204 can be used for various reasons, but it is preferred that port 204is used as a telescopic video port which will provide video assistanceduring the procedure. While under endoscopic observation, a secondincision is made in the third or fourth intercostal space at theanterior axillary line that is identified as port 206. Port 206 ispreferably used as an instrument channel. A third incision is made atthe posterior axillary line just below the scapular tip in the fifthinterspace that is identified as port 202. Port 206 is preferably usedas a second instrument channel. Preferably, the three incisions madeduring the thoracoscopic sympathectomy are approximately 2 cm in length.Additional incisions (i.e., ports) can be made as necessary.

Referring to FIGS. 5 and 6, in which axial cross section and exposedviews of the surgical sites are provided, respectively, the surgicalexposure and preparation of the relevant portion of the sympatheticnerve chain for the treatment of various physiological and pathologicalconditions is described. After the lung 210 is collapsed, and ifnecessary, retracted down by a fanning instrument via one of the workingports, the sympathetic nerve chain 212 is visualized under the parietalpleura 214 as a raised longitudinal structure located at the junction ofthe ribs 216 and the vertebral bodies 218. The parietal pleura 214 isgrasped between the first and second ribs in the region overlying thesympathetic nerve chain 212 and scissors 220 or endoscopic cautery isused to incise the parietal pleura 214 in a vertical manner just belowthe first rib thereby exposing the sympathetic nerve chain 212.

Referring now to FIG. 7, in which the implantation of a multichannelstimulation lead 222 at a specific location of the sympathetic nervechain is shown, the implantation of the stimulation lead 222 is nowdescribed. Once the sympathetic nerve chain 212 has been exposed, amultichannel stimulation lead 222 is implanted adjacent to apredetermined site along the sympathetic nerve chain that is associatedwith the physiological disorder or pathological condition being treated.The stimulation lead 222 is sutured in place to the nearby tissue orparietal pleura 214. The vicinity of the sympathetic nerve chain forwhich the stimulation lead is positioned depends on the physiologicaldisorder or pathological condition being treated.

The influence of the neuromodulation of the systems and methods of thepresent invention can be manifested as changes in biological activity.For example with respect to treating cardiovascular medical conditions,such changes include changes in heart rate, heart rhythm, blood flow tothe heart and cardiac contractility. These changes are reflectedphysiologically by parameters such as, for example, heart rate, bloodpressure, cardiac output, stroke volume, pulmonary wedge pressure, andvenous pressure, all of which can be measured. Preferably, theneuromodulation allows for selective changes in one or more aspects ofthe target organ whose function is being influenced without influencingor minimally influencing other functions of the target organ. Forexample, cardiac function may be selectively influenced by varying theparameters of stimulation such that cardiac contractility is affectedbut not heart rate.

The influence of neuromodulation of this method of the present inventionon the respiratory system, for example, can be manifested in respiratoryrate, changes in elasticity of the lung tissue, changes in diameter ofthe bronchioles and other structures in the respiratory branches,perfusion and diffusion of blood and its products at the level of thealveoli and blood flow to the lungs. These changes are reflectedphysiologically by parameters such as, for example, respiratory rate, pHof blood, bicarbonate level, ventilatory volume, lung capacity, andblood oxygenation.

The foregoing description has been set forth merely to illustrate theinvention and isnot intended as being limiting. Each of the disclosedaspects and embodiments of the present invention may be consideredindividually or in combination with other aspects, embodiments, andvariations of the invention. In addition, unless otherwise specified,none of the steps of the methods of the present invention are confinedto any particular order of performance. Modifications of the disclosedembodiments incorporating the spirit and substance of the invention mayoccur to persons skilled in the art and such modifications are withinthe scope of the present invention. For example, although methods oftreating specific medical conditions are described with respect toelectrical and chemical neuromodulation, other modes of neuromodulationcan be used such as light, magnetism, sound, pressure, and heat/cold.Furthermore, all references cited herein are incorporated by referencein their entirety.

TABLE I TYPE OF DISORDER/MEDICAL CONDITION TYPE OF SENSING PERFORMEDSKELETAL DISORDERS osteomalacia Radiographic, magnetic resonanceimaging, computer tomography, bone densitometry, presence of effusion injoints or surrounding tissue, protein concentration and/or content inthe joint or surrounding tissue, autoantibodies, antinuclear antibody,antibodies to double-stranded DNA, depressed serum complement,rheumatoid factor, creatine kinase, antinuclear antibodies, erythrocytesedimentation rate C-reactive protein, uric acid arthritis fracturesosteoporosis osteopenia osteonecrosis infectious arthritis TenosynovitisBursitis CONNECTIVE TISSUE/RHEUMATOLOGICAL DISORDERS rheumatoidarthritis Radiographic, magnetic resonance imaging, computer tomography,bone densitometry, presence of effusion in joints or surrounding tissue,protein concentration and/or content in the joint or surrounding tissue,autoantibodies, antinuclear antibody, antibodies to double-stranded DNA,depressed serum complement, rheumatoid factor, creatine kinase,antinuclear antibodies, erythrocyte sedimentation rate C-reactiveprotein, uric acid, venous pressure, Temperature, blood pressure, heartrate, pH of blood, blood oxygenation level, oxygen saturation level,blood viscosity polymyositis/dermatomyositis scleroderma gout rheumaticfever Reiter's syndrome systemic lupus erythematosus myalgias/myopathyvasculitis syndrome Sjögren's syndrome rhabdomyolysis seronegativespondyloarthropathies Polymyalgia Rheumatica VASCULAR DISORDERS arterialaneurysms Ultrasonography, echocardiogram, angiography, skin color,temperature, pain, neurological manifestation, presence and degree ofedema, blood pressure, heart rate, urinary output, oxygen pressure inblood and/or tissues, venous pressure, temperature, blood pressure,heart rate, pH of blood, blood oxygenation level, oxygen saturationlevel, blood viscosity aortic dissection venous occlusive diseaseBuerger's disease Arteritis obliterans arterial occlusive diseaseTakayasu's disease fibromuscular dysplasia Raynaud's syndrome livedoreticularis acrocyanosis erythromelalgia acute deep venous thrombosisDeep venous thrombosis chronic venous insufficiency lymphangitis andlymphadenitis lymphedema Thrombocytosis Thrombocytopenia ThrombosisArterial Dissection Peripheral edema Blood Loss Vascular insufficiencyhypercoagulable states hypotension and shock HEMATOLOGICAL DISORDERSHematocrit, neutrophil count, white count, platelet count, red cellmorphology, LDH, bleeding time, factor VIII antigen, factor VIIIcoagulant activity, platelet function, prothrombin time, partialthromboplastin time, prothrombin time-international normalized ratio,bleeding time, factor IX levels fibrin degradation products, andprothrombin time, venous pressure, temperature, blood pressure, heartrate, pH of blood, blood oxygenation level, oxygen saturation level,blood viscosity neutropenia leukemias and other myeloproliferativedisorders lymphomas idiopathic thrombocytopenic purpura heparin-inducedthrombocytopenia thrombotic thrombocytopenic purpura von Willebrand'sdisease disorders intrinsic to the platelets uremia myeloproliferativedisorders hemophilia A hemophilia B syndrome of disseminatedintravascular coagulation hemolytic transfusion reactions Sickle CellAnemia anemia Hodgkin's disease ALLERGIC DISORDERS specific-IgE antibodyto tested aeroallergens, serum tryptase, immune complexes in serum ordeposited in affected tissues, venous pressure, Temperature, antibodylevels of immunoglobulin(Ig) M, IgG, IgA, blood pressure, heart rate, pHof blood, blood oxygenation level, oxygen saturation level, bloodviscosity Environmental Allergy Hypogamaglobunimia angioedema urticariaallergic rhinitis anaphylaxis drug allergy serum sickness amyloidosisNEUROLOGICAL DISORDERS clinical symptons and neurological exam, subduralelectrodes over the brain and/or brainstem and/or spinal cord to measureelectrical activity of the brain and/or spinal cord and/or brain stem,cerebrospinal fluid (CSF) pressure, cerebrospinal fluid protein and/orglucose and/or cell count, electroencephalogram, neuronal electricalactivity, transcranial magnetic stimulation, myelin basic protein incerebrospinal fluid, cerebrospinal fluid production rate, somatosensoryand/or visual and/or auditory evoked potential, single fiberelectromyography, surface electromyography of the muscle tissue skin,skin temperature, heart rate, sweating, intestinal motility, sphinctercontrol, sexual function, respiratory rate, flicker pupilary response,oximetry, transcranial Doppler, accelerometer, acetylcholine antibodiesin blood Alzheimers disease cerebral Palsy Intracerebral hemorrhageDiplopia Cerebral Vasospasm Amyotrophic lateral sclerosis Multiplesclerosis Aneurysm Atriovenous Malformation Brain MalformationsMulti-system atrophy Olivopontocerebellar Dystonia TorticollisBlepharospasms Spasmodic dyshponia Radiculopathy Neuropathy postherpeticneuralgia on the head, body, trunk, chest or extremities epilepsydysautonomia restless leg syndrome Carpal tunnel syndrome Tarsal tunnelsyndrome epicondylitis Subclavian steel syndrome Isolated centralnervous system vasculitis Systemic vasculitis Encephalitis from variouscauses including but not limited to Neoplastic, auto immune, infectious,etc. Meningitis including but not limited to infectious, chemical,Neoplastic, drug induced arachnoiditis cerebritis sensory disturbancesin any combination (allodynia, paresthesia dysesthesia, anesthesia)Sensory loss in any combination (vibration, proprioception, temperature,light touch, pain) weakness and paralysis stroke subarachnoid hemorrhagebenign essential (familial) tremor Parkinsonism Huntington's diseasedementia multiple sclerosis stupor and coma spinal trauma motor neurondiseases Acute Idiopathic Polyneuropathy (Guillain- Barré Syndrome)Myasthenia Gravis Myasthenic Syndrome (Lambert-Eaton Syndrome) Autismhydrocephalus neuropathy Sleep apnea insomnia Snoring EAR, NOSE andTHROAT DISORDERS clinical examination audiology, caloric stimulation,electronystagmography, Radiographic, magnetic resonance imaging,computer tomography, brain stem auditory evoked potential studies, testolfaction Dizziness Loss of sense of smell rhinorrhea nasal congestionhearing loss external otitis auditory tube dysfunction acute otitismedia tinnitus vertigo vestibular schwannoma (Acoustic Neuroma) acutesinusitis involving one or more sinuses including sphenoid, maxillary,ethmoid, frontal olfactory dysfunction epistaxis glossitis glossodyniaburning mouth syndrome dysgeusia pharyngitis and tonsillitisepiglottitis Ménière's disease Chronic Sinusitis Deviated nasal septumIntranasal polyps RESPIRATORY DISORDERS Spirometry, measurement of airmovement throughout the respiratory tree via external or internal placesensors to measure forced vital lung capacity, total lung capacity,forced expiratory lung volume, residual lung volume before and/or afterthe administration of a short-acting bronchodilator, Peak expiratoryflow meters, arterial blood gas, D-dimer, venous pressure, Temperature,blood pressure, heart rate, pH of blood, blood oxygenation level, oxygensaturation level, blood viscosity,, diaphragmatic movement, chest wallexpansion measured by a strain gauge asthma chronic obstructivepulmonary disease (COPD) cystic fibrosis bronchiolitis pneumoniapulmonary thromboembolism Bronchitis Emphysema Adult respiratorydistress syndrome Allergies Brochiectasis Bronchopulmonary dysplasiaChlamydia pneumoniae Chronic Bronchitis Chronic lower respiratorydiseases Croup Familial emphysema High altitude pulmonary edemaIdiopathic Pulmonary Fibrosis Interstitial lung diseaseLymphangioleiomyomatosis Neonatal Respiratory Distress SyndromeParainfluenza Pleural effusion Pleurisy Pneumothorax Primary pulmonaryhypertension Psittacosis Pulmonary edema Pulmonary embolism Pulmonaryhypertension Q fever Respiratory failure Respiratory syncytial virusSarcoidosis SARS Smoking Stridor Tuberculosis acute respiratory distresssyndrome (ARDS) CARDIAC DISORDERS Echocardiogram, blood pressure, heartrate, stroke volume, electrocardiogram, coronary angiogram, angioscopy,cardiac contractility measured by myography, cardiac biopsy, pulmonarywedge pressure, venous pressure, Temperature, blood pressure, heartrate, pH of blood, blood oxygenation level, oxygen saturation level,blood viscosity, congenital heart disease valvular heart diseaseincluding stenotic and/or insufficency atherosclerotic coronary arterydisease Arrhythmias including but not limited to atrial fibrillation,ventricular Fibrillation, atrial flutter, ventricular flutter,tachycardia, bradycardia Tachy-brady syndrome, skipped beats, firstdegree heart block, Second degree heart block, atriovenous node blockinfectious myocarditis Ischemic heart disease Heart murmurs Rheumaticheart disease Hypertensive heart disease Ischemic stroke Hemorrhagicstroke Cortical stroke Sub cortical stroke Cerebral anoxia Cerebellarstroke Brain stem stroke. Atherosclerosis Angina CerebralArteriosclerosis Autoimmune Atherosclerosis Peripheral arterial diseaseHypertension Heart failure right and/or left Atrial septal defectVentricular septal defect Arterial dissection in the carorid and/orbasilar and/or vertebral And/or aorta and/or renal arteries Septalaneurysm Microvascular ischemia GASTROINTESTINAL DISORDERS esophagealdysphagia esophageal manometry, barium esophagogram, esophagography,endoscopy, receptor scintigraphy (SRS) and endoscopic ultrasonography,endoscopic mucosal biopsy, Plain film radiography, comuter tomography,colonoscopy, measurement of the surface and/or deep muscle tone ofesophagus, stomach, large and small intestine, colon, rectum,measurement of discharges of nerve plexus (myenteric) in the muscle wallof colon, intestine, stomach pH, peristaltic wave measurement includingfrequency and duration, small bowel manometry, serum lipase, serumamylase, gastrin level, pepsin, chloride level, vasoactive intestinalpeptide level esophageal diverticula esophageal motility disordersZollinger-Ellison syndrome celiac disease intestinal motility disordersgastroparesis chronic intestinal pseudo- obstruction irritable bowelsyndrome colonic diverticulosis Chronic digestive diseases inflammatorybowel disease Crohn's disease ulcerative colitis gastroparesis diabeticgastroparesis diabetic diarrhea Celiac disease Lactose IntoleranceCystic Fibrosis Esophagitis Gastroesophageal reflux disease GastritisDiarrhea Abdominal cramps constipation cholecystitis Biliary stasisAscites Hepatic failure Cirrhosis Hepatic encephalopathy Hepatitis acuteand/or chronic gastroenteritis Achalasia gas Acute Nonulcer dyspepsiaAcute Pancreatitis Amebic dysentery Anthrax Bacterial digestiveinfections Behcet's Disease Bowel Obstruction Carcinoid ofGastrointestinal Tract Cholera Chronic Nonulcer dyspepsia ChronicPancreatitis Colonic volvulus Colorectal cancer CryptosporiosisDysentery Entamoeba histolytica Enterocolitis Food intolerancesGallstones Gastric erosion Gastrointestinal Anthrax Giardia MigraineEquivalent dyspepsia Helicobacter pylori bacteria Hemolytic uremicsyndrome Hirschsprung's disease Indigestion Intestinalpseudo-obstruction Megacolon Nonulcer dyspepsia Pancreatitis PepticUlcer Pyloric stenosis Rapid gastric emptying Dumping syndromeShigellosis Small Intestine Cancer Sprue Stomach Cancer Viral digestiveinfections Viral dysentery Viral gastroenteritis Whipple's DiseaseEnteroviruses Malabsorption Class I obesity - basal metabolic index of30-34.9 Class II obesity- basal metabolic index of 35-39.9 Class IIIobesity- basal metabolic index of 40 and higher IMMUNOLOGICAL DISORDERSRadiographic, magnetic resonance imaging, computer tomography, bonedensitometry, presence of effusion in joints or surrounding tissue,protein concentration and/or content in the joint or surrounding tissue,autoantibodies, antinuclear antibody, antibodies to double-stranded DNA,depressed serum complement, rheumatoid factor, creatine kinase,antinuclear antibodies, erythrocyte sedimentation rate C-reactiveprotein, uric acid, specific-IgE antibody to tested aeroallergens, serumtryptase, immune complexes in serum or deposited in affected tissuesRheumatoid arthritis Autoimmune thyroid diseases Graves DiseaseHashimoto's Thyroiditis Systemic Lupus Erythematosus Multiple SclerosisCrohn's disease Psoriasis Psoriatic Arthritis Sympathetic ophthalmitisAutoimmune neuropathies Autoimmune oophoritis Autoimmune orchitisAutoimmune Lymphoproliferative Syndrome Antiphospholipid syndromeSjogren's Syndrome Rheumatoid arthritis Scleroderma Lupus Addison'sDisease Polyendocrine deficiency syndrome Polyendocrine deficiencysyndrome type 1 Polyendocrine deficiency syndrome type 2 Guillain-BarreSyndrome Immune Thrombocytopenic Purpura Pernicious anemia MyastheniaGravis Primary biliary cirrhosis Mixed connective tissue disease PrimaryGlomerulonephritis Vitiligo Autoimmune uveitis Autoimmune HemolyticAnemia Autoimmune Thrombocytopenia Celiac Disease Dermatitisherpetiformis Autoimmune Hepatitis Pemphigus Pemphigus VulgarisPemphigus Foliaceus Bullous Pemphigoid Autoimmune Myocarditis AutoimmuneVasculitis Autoimmune eye diseases Alopecia Areata AutoimmuneAtherosclerosis Behcet's Disease Autoimmune Myelopathy AutoimmuneHemophilia Autoimmune Interstitial Cystitis Autoimmune DiabetesInsipidus Autoimmune Endometriosis Relapsing Polychondritis AnkylosingSpondylitis Autoimmune Urticaria Paraneoplastic Autoimmune SyndromesDermatomyositis Miller Fisher Syndrome IgA nephropathy Goodpasturesyndrome Herpes gestationis OCULAR DISORDERS Myopia HyperopiaAstigmatism Corneal ulcer cataracts glaucoma-narrow angle or open anglediplopia macular degenaration retinal dystrophy Corneal flash burnsCorneal abrasion retinitis pigmentosa amblyopia strabismus CornealDystrophies Fuchs' Dystrophy keratoconus lattice dystrophymap-dot-fingerprint dystrophy Presbyopia Age-related maculardegeneration Uveitis Blindness DERMATOLOGICAL DISORDERS Acne RosaceaEczema Psoriasis Hair Loss Hypertrichosis Seborrheic dermatitis XeroticSkin Oily Skin Wrinkles Cellulite Vitiligo Radation induced damageurticaria ENDOCRINOLOGICAL DISORDERS Insulin Resistance MetabolicSyndrome Diabetes Type 2 Diabetes Type 1 diabetes impaired glucosetolerance Autoimmune diseases Autoimmune diseases Obesity hypoglycemiahyperthyroidism hypothyroidism amenorrhea dysmenorrhea perimenstrualsyndrome hypercholesterolemia hypertriglycridinemia Cushing's diseaseAddison's disease malabsorption syndrome cold extremities hot flashesheat exhaustion Raynaud's syndrome hormonal disorders gout metabolicstorage diseases GENITOURINARY DISORDERS Impotence Urinary IncontinenceCystitis Infertility Kidney conditions Kidney disease Kidney stonesGlomerular Disease Glomerulonephritis Glomerulosclerosis (type ofGlomerular Disease) Kidney cancer Diabetic nephropathy Lupus nephritisend-stage renal disease kidney failure Acute kidney failure IgAnephropathy Acute urinary conditions Urinary tract infections Urinarytract infections (child) Pyelonephritis nephrotic syndrome Childhoodnephrotic syndrome Post streptococcal glomerulonephritis Goodpasturesyndrome Nephrocalcinosis Kidney cysts Simple kidney cysts polycystickidney disease Acquired Cystic Kidney Disease Autosomal dominantpolycystic kidney disease Autosomal Recessive Polycystic Kidney DiseaseDiabetes Insipidus Autoimmune Diabetes Insipidus Alveolar HydatidDisease Kidney Dialysis Primary amyloidosis Dialysis-related amyloidosisHematuria Proteinuria Renal Tubular Acidosis Proximal Renal TubularAcidosis Renal carbuncle Renal osteodystrophy Renal tuberculosisTuberculosis Tuberous sclerosis Vesicoureteral reflux Wegener'sgranulomatosis Wilms' tumor Wilson's Disease Zellweger Syndrome Chronickidney failure Nephritis Nephropathy Bladder Incontinence (Pregnancy)Penile candidiasis Polycystic kidney disease Delayed orgasm flaccidbladder spastic bladder Interstitial cystitis RENAL DISORDERShydrostatic pressure in renal tubular, glomerular filtration rate,electrolytes concentration including sodium, potassium and calcium inthe tubules and renal vasculature, renin levels, aldosterone levels,erythropoietin levels, perfusion pressure, muscle tone of the bladdermeasured by myography, size of the bladder, hydrostatic pressure insideand outside the bladder PSYCHOLOGICAL DISORDERS Insomnia Sleep disordersDepressive disorders depression clinical depression Dysthymia Bipolardisorder Alcoholism Schizophrenia Nonaffective Psychosis SomatizationTourettes autism mental retardation delusions Smoking Stress AnorexiaNervosa Alcohol abuse Phobias Anti-Social Personality DisorderBorderline Personality Disorder Social phobia Eating disorders Learningdisabilities addiction to illicit drugs addiction to alcohol Drug abuseGeneralized anxiety disorder Attention Deficit Hyperactivity DisorderObsessive-compulsive disorder Agoraphobia Bipolar disorder Panicdisorder addictive behavior such as gambling, sex Bulimia nervosa Bingeeating disorder INFLAMMATORY DISORDERS Irritable Bowel Syndrome Crohn'sdisease PAIN DISORDERS migraine headaches with aura migraine headacheswithout aura menstrual migraines migraine variants atypical migrainescomplicated migraines hemiplegic migraines transformed migraines andchronic daily migraines episodic tension headaches chronic tensionheadaches analgesic rebound headaches episodic cluster headaches chroniccluster headaches cluster variants chronic paroxysmal hemicraniahemicrania continua post-traumatic headache post-traumatic neck painpost-herpetic neuralgia involving the head or face pain from spinefracture secondary to osteoporosis arthritis pain in the spine headacherelated to cerebrovascular disease and stroke headache due to vasculardisorder reflex sympathetic dystrophy cervicalgia glossodyniacarotidynia cricoidynia otalgia due to middle ear lesion gastric painsciatica maxillary neuralgia laryngeal pain myalgia of neck musclestrigeminal neuralgia post-lumbar puncture headache low cerebro-spinalfluid pressure headache temporomandibular joint disorder atypical facialpain ciliary neuralgia paratrigeminal neuralgia petrosal neuralgiaEagle's syndrome idiopathic intracranial hypertension orofacial painmyofascial pain syndrome involving the head myofascial pain syndromeinvolving the neck myofascial pain syndrome involving the shoulder myfactual pain syndrome involving the back chronic migraneous neuralgiacervical headache paratrigeminal paralysis sphenopalatine ganglionneuralgia carotidynia Vidian neuralgia causalgia back pain fibromyalgiachronic fatigue syndrome METABOLIC STORAGE DISEASES lysosomal storagedisorders lipid storage diseases glycogen storage diseases NEOPLASTICDISORDERS metastatic cancer benign growths Aging Process RadiationInduced Damage Adjunct to conventional therapy including medicationand/or surgery and/or psychiatric Enhancement of treatment efficacyLimiting and minimizing adverse reaction and side effects Hastenrecovery Enhancement of Normal Function and Physiology Improvecoordination Enhance memory Increase physical endurance Increase musclestrength Increase speed in mobility Cosmetics Breast enhancement BreastReduction Removal of wrinkles of face, neck and body Reduce fat aroundwaist line Flatten stomach Increase resting muscle tone to abdominalmuscles Improve muscle tone in buttocks Reduce and/or resolve celluliteenhance calf muscles

1-16. (canceled)
 17. A method of alleviating an endocrinologicalcondition in a patient suffering therefrom, said method comprising thesteps of: placing an electrode in electrical contact with a target siteof the patient, the target site being in communication with asympathetic nerve chain (SNC); detecting a bodily activity associatedwith the endocrinological condition via a sensor and generating a sensorsignal; and activating the electrode to initiate application of anelectrical signal to the target site in response to the sensor signal oradjusting application of an electrical signal to the target site inresponse to the sensor signal to alleviate the patient'sendocrinological disorder; wherein the electrical signal has a voltagerange of 0.1 μV to about 20 V and a frequency range of about 2 Hz toabout 2500 Hz.
 18. The method of claim 17, wherein the endocrinologicaldisorder is related to the pancreas or the liver of the patient.
 19. Themethod of claim 18, wherein the endocrinological disorder is at leastone of hypoglycemia, Type I diabetes, Type II diabetes, or obesity. 20.The method of claim 17, wherein the target site is a sympatheticganglion.
 21. The method of claim 20, wherein the sympathetic ganglionis a T5-T12 ganglion.
 22. The method of claim 20, wherein thesympathetic ganglion is at least one of a superior cervical ganglion, amiddle cervical ganglion, an inferior cervical ganglion, or acervicothoracic ganglion.
 23. The method of claim 17, wherein the bodilyactivity associated with the endocrinological condition is the level ofat least one of glucose, liver enzymes, electrolytes, or hormones in thepatient.
 24. A method for alleviating an endocrinological conditionrelated to the pancreas or liver of a patient suffering therefrom, saidmethod comprising the steps of: placing an electrode in electricalcontact with a target site of the patient, the target site comprising atleast one thoracic or cervical ganglion of the SNC; detecting a bodilyactivity associated with the endocrinological condition via a sensor andgenerating a sensor signal, the bodily activity associated with theendocrinological condition being the level of at least one of glucose,liver enzymes, electrolytes, or hormones in the patient; and activatingthe electrode to initiate application of an electrical signal to thetarget site in response to the sensor signal or adjusting application ofan electrical signal to the target site in response to the sensor signalto alleviate the patient's endocrinological disorder; wherein theelectrical signal has a voltage range of 0.1 μV to about 20 V and afrequency range of about 2 Hz to about 2500 Hz.
 25. The method of claim24, wherein the endocrinological disorder related to the pancreas orliver is at least one of hypoglycemia, Type I diabetes, Type IIdiabetes, or obesity.
 26. The method of claim 24, wherein the thoracicganglion is a T5-T12 ganglion.
 27. The method of claim 24, wherein thecervical ganglion is at least one of a superior cervical ganglion, amiddle cervical ganglion, an inferior cervical ganglion, or acervicothoracic ganglion.
 28. A method for alleviating anendocrinological condition related to the pancreas or liver of a patientsuffering therefrom, said method comprising the steps of: placing anelectrode in electrical contact with a target site of the patient, thetarget site comprising at least one of a superior cervical ganglion, amiddle cervical ganglion, an inferior cervical ganglion, or acervicothoracic ganglion; detecting a bodily activity associated withthe endocrinological condition via a sensor and generating a sensorsignal, the bodily activity associated with the endocrinologicalcondition being the level of at least one of glucose, liver enzymes,electrolytes, or hormones in the patient; and activating the electrodeto initiate application of an electrical signal to the target site inresponse to the sensor signal or adjusting application of an electricalsignal to the target site in response to the sensor signal to alleviatethe patient's endocrinological disorder; wherein the electrical signalhas a voltage range of 0.1 μV to about 20 V and a frequency range ofabout 2 Hz to about 2500 Hz; wherein the endocrinological disorderrelated to the pancreas or liver is at least one of hypoglycemia, Type Idiabetes, Type II diabetes, or obesity.